Acute Myeloid Leukemia (AML) is a cancer affecting the blood and bone marrow, characterized by the rapid growth of abnormal myeloid cells. It requires medical intervention to manage its progression and improve patient outcomes. AML management relies on various therapeutic approaches, including traditional chemotherapy, targeted therapies, immunotherapy, and stem cell transplantation. These methods often combine to achieve the best results.
Traditional Chemotherapy
Conventional chemotherapy remains a primary treatment for many types of AML. These medicines attack rapidly dividing cells throughout the body, a characteristic shared by leukemia cells. Treatment typically involves two main phases: induction therapy and consolidation therapy.
Induction Therapy
Induction therapy is the initial phase, aiming to eliminate leukemia cells from the blood and bone marrow to achieve remission. A common regimen, “7+3,” involves continuous intravenous infusion of cytarabine for seven days, combined with an anthracycline drug like daunorubicin or idarubicin for the first three days. This intensive approach clears detectable leukemia cells, allowing the bone marrow to recover and produce healthy blood cells. The goal is complete remission, where no leukemia cells are found.
Consolidation Therapy
Once remission is achieved, consolidation therapy follows to prevent the disease from returning. This phase targets any remaining leukemia cells that may not have been eradicated during induction. High-dose cytarabine (HiDAC) is a frequently used medication in this phase, often administered in several cycles. Other combinations may include cytarabine with daunorubicin or liposomal cytarabine and daunorubicin (CPX-351). These cycles reduce the risk of relapse.
Targeted Therapies
Targeted therapies offer a precise approach to treating AML by focusing on specific molecular abnormalities within leukemia cells. These medicines identify and attack particular proteins or pathways that drive cancer growth, often based on genetic mutations. This specificity helps minimize harm to healthy cells compared to traditional chemotherapy.
FLT3 Inhibitors
One common target is the FMS-like tyrosine kinase 3 (FLT3) gene, which, when mutated, can cause leukemia cells to grow excessively. FLT3 inhibitors, such as midostaurin, quizartinib, and gilteritinib, block the activity of this mutated protein. Midostaurin is often used alongside chemotherapy for newly diagnosed patients with FLT3 mutations, while gilteritinib is approved for relapsed or refractory AML with FLT3 mutations.
IDH1/IDH2 Inhibitors
Another set of targets involves mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 genes, found in about 10-20% of AML cases. These mutations lead to an abnormal metabolite that interferes with normal cell maturation. Ivosidenib specifically targets mutated IDH1, while enasidenib targets mutated IDH2, helping restore normal blood cell differentiation. These inhibitors are often used for patients with relapsed or refractory AML, or for those unable to tolerate intensive chemotherapy.
BCL-2 and CD33 Targeting
A different targeted approach involves agents like venetoclax, which inhibits the BCL-2 protein. BCL-2 helps cancer cells survive, and blocking it can trigger cell death. Venetoclax is often combined with low-dose chemotherapy drugs like azacitidine or low-dose cytarabine, particularly for older patients or those unable to tolerate intensive chemotherapy. Gemtuzumab ozogamicin is an antibody-drug conjugate that targets the CD33 protein found on most AML cells. This antibody delivers a chemotherapy drug directly to leukemia cells, reducing systemic toxicity.
Immunotherapy Approaches
Immunotherapy represents a distinct class of AML medicines that leverage or enhance the body’s own immune system to identify and destroy cancer cells. Unlike chemotherapy or targeted drugs that directly attack cancer cells, immunotherapy aims to empower the patient’s immune response. While successful in other cancers, its application in AML is continuously evolving.
Monoclonal Antibodies
One strategy involves monoclonal antibodies, which are laboratory-made immune proteins designed to bind to specific targets on cancer cells. Other monoclonal antibodies are being investigated that target different proteins on AML cells, such as CD123 or CD47, aiming to either directly kill the cells or block signals that protect them from immune attack.
CAR T-cell Therapy
Another area of research in AML immunotherapy includes Chimeric Antigen Receptor (CAR) T-cell therapy, which has shown promise in other blood cancers. This therapy involves extracting a patient’s T-cells, genetically modifying them to express CARs that recognize specific antigens on leukemia cells, and then reinfusing them. While CAR T-cell therapy for AML faces challenges due to shared antigens between leukemia cells and healthy blood-forming cells, ongoing research explores strategies like targeting multiple antigens to improve safety and efficacy.
Stem Cell Transplantation
Stem cell transplantation, also known as bone marrow transplant, is a potentially curative treatment for AML. This procedure involves replacing diseased bone marrow with healthy stem cells, relying on high-dose chemotherapy as a preparatory step. This intensive conditioning regimen eliminates remaining cancer cells and suppresses the patient’s immune system to prevent rejection of transplanted cells.
Conditioning Regimen
The conditioning regimen typically involves very high doses of chemotherapy, sometimes combined with total body radiation therapy, administered over several days. A common myeloablative conditioning regimen might include high-dose cytarabine along with other chemotherapy drugs like busulfan or melphalan. This aggressive treatment aims to destroy all existing bone marrow, including any residual leukemia cells. Younger and healthier patients are candidates for these intensive myeloablative regimens due to their ability to tolerate significant side effects.
Stem Cell Infusion
Following conditioning therapy, healthy blood-forming stem cells, usually from a matched donor (allogeneic transplant), are infused. These new stem cells travel to the bone marrow, where they engraft and begin producing healthy blood cells, effectively replacing the diseased marrow. In some cases, a “mini-transplant” or reduced-intensity conditioning regimen may be used for older or less fit patients. This involves lower doses of chemotherapy that suppress the immune system without completely destroying the bone marrow, allowing donor cells to establish a new immune system that can recognize and attack any remaining leukemia cells, a phenomenon known as the graft-versus-leukemia effect.